The long-term objective of this Project is to determine the natural history of monoclonal gammopathy of undetermined significance (MGUS). We will determine the prevalence of MGUS in Olmsted County, Minnesota and then follow asymptomatic prevalence cases as well as MGUS patients previously recognized clinically in a prospective study. To ascertain long-term outcome, we will also conduct a retrospective cohort study using clinically recognized mGUS patients. Although the quality of medical information in the Olmsted County population is excellent, the relatively small population (106,000) poses some problems in obtaining enough cases for determining the natural course of diseases of relatively low frequency. Therefore, we will expand the study population to include cases from the remaining 10 Southeastern Minnesota counties. This is justified by the similarity of MGUS patients in Olmsted County and Southeastern Minnesota on the basis of their age, sex, race, size and type of M-protein found in our earlier surveys. All cases of MGUS from the entire Southeastern Minnesota area diagnosed from 1956 through 1994 will be followed in a retrospective cohort study for survival and risk of multiple myeloma, macroglobulinemia, primary amyloidosis, and other plasma cell proliferative disorders. We will follow the survivors of the Southeastern Minnesota MGUS cohort that has been followed retrospectively and new cases recognized after January 1, 1995 annually in a prospective study to determine the factors associated with progression of MGUS to multiple myeloma and related disorders. This project will also provide bone marrow and peripheral blood to Projects II and III in order to investigate the molecular events in the transition of MGUS to multiple myeloma. This includes determination of IL-6, IL-1, and sIL-6R mRNA expression and serum levels of IL-6 and sIL-6R in patients with MGUS and active multiple myeloma (Project II). The studies described in Project III extend those of Project II by examining specific mechanisms that may account for increased IL-6 production by the tumor itself such as aberrant signaling and response to CD40 stimulation or deregulation of pRb1. The potential to study patients with MGUS that progress to myeloma from serial samples obtained through Project I will provide extremely valuable information about the role of Il-6 in the progression of MGUS to myeloma. Peripheral blood will be studied for the presence of circulating myeloma cells in both MGUS and MM (Project IV). Hopefully, a better understanding of the molecular events underlying the progression of MGUS will result in the development of approaches to interfere with this progression.